Androstenedione is a C.sub.19 steroid of the formula: ##STR1##
Androsta-4,9(11)-diene-3,17-dione refers to androstenedione with a double bond between carbon atoms 9 and 11. Androsta-4,9(11)-dienes 3,17-dione type compounds refer to steroids within the scope of formula III: ##STR2## R.sub.6, R.sub.16 and .about. are defined infra.
The -androsta-4,9(11)-diene-3,17-dione-type compounds (III) are useful for producing pharmaceuticals, in particular testosterone derivatives. For example, androsta-4,9(11)-diene-3,17-dione (III) is converted to 3-(N-pyrrolidinyl)androsta-3,5,9(11)-trien-17-one to protect the C.sub.3 ketone by the process disclosed by F. W. Heyl and M. E. Herr in J. Am. Chem. Soc. 77, 488 (1955). This protected steroid is converted to 17.beta.-hydroxy-17-methyl androsta-4,9(11)-diene-3-one by a Grignard reaction with methylmagnesium bromide and subsequent alkaline hydrolysis. See M. E. Herr et al., J. Am. Chem. Soc. 78, 500 (1956). This methyltestosterone derivative is then converted to 9.alpha.-fluoro-11.beta.,17.beta.-dihydroxy-17-methyl androsta-4-ene-3-one (fluoxymesterone, Halotestin.RTM.) which is a commercially marketed steroid, by the process of U.S. Pat. No. 3,118,880, Example 2.
The .DELTA..sup.9(11) -steroids have been prepared from both 11.beta.-hydroxy steroids and 9.alpha.-hydroxy steroids. George G. Hazen and D. W. Rosenburg, J. Org. Chem. 29, 1930 (1964); D. Taub et al., J. Am. Chem. Soc. 82, 4102 (1960); E. M. Chamberlin, J. Org. Chem. 25, 295 (1960); T. Reichstein, U.S. Pat. No. 2,409,798, Drake, U.S. Pat. No. 3,005,834, and Great Britain Pat. No. 1,198,749 all disclose synthesis of .DELTA..sup.9(11) -steroids from 11.beta.-hydroxy steroids. The papers by Hazen, Taub, and Chamberlin all disclose using 11.beta.-hydroxy corticoids to form the corresponding .DELTA..sup.9(11) -corticoids. U.S. Pat. Nos. 2,409,798 (Example 3),3,005,834 (Example 35) and Great Britain Pat. No. 1,198,749 (Example 1) disclose the use of 11.beta.-hydroxy androstenes to produce .DELTA..sup.9(11) -androstenes.
While 11.beta.-hydroxy steroids have been used to synthesize the corresponding .DELTA..sup.9 (11)-steroids, the process of the present invention involves sulfinylation then desulfinylation of 9.alpha.-hydroxyandrostenedione-type steroids (I) to form the corresponding androsta4,9(11)-diene-3,17-dione-type steroids (III).
.DELTA..sup.9(11) -Steroids have previously been prepared from the corresponding 9.alpha.-hydroxy steroids.
J. Fried et al., Tetrahedron Letters, 13, 849 (1965) disclosed the use of thionyl chloride in pyridine for forming .DELTA..sup.9(11) -steroids from the corresponding 9.alpha.-hydroxy tetracyclic triterpene in approximately an 80% yield. C. J. Sih, U.S. Pat. No. 3,065,146 also disclosed using thionyl chloride in pyridine. U.S. Pat. No. 3,065,146 (Example 7, paragraph 1) discloses the preparation of .DELTA..sup.9(11) -dehydroprogesterone. Paragraph 2 states: "In the same manner, following the procedure of example 7...9.alpha.-hydroxy-.DELTA..sup.4 -androstene-3,17-dione . . . (is) converted to . . . .DELTA..sup.4,9(11) -androstene-3,17-dione . . ."
No physical data is given for the product, .DELTA..sup.4,9(11) -androstene-3,17-dione. The applicant has performed this reaction obtaining the product in approximately 50% yield. See Preparations 1 thru 3. The reaction produces a 50--50 mixture of the isomeric .DELTA..sup.9(11) - and the .DELTA..sup.8 -olefins. The highest yield obtained of the .DELTA..sup.9(11) -isomer was 55.5% (Example 3). These isomeric olefins had the same R.sub.f 's on TLC and could not be separated by crystallization. In addition to the very difficult if not impossible separation problem there is the obvious problem that one obtains only approximately 50% of the desired product.
U.S. Pat. No. 3,005,834 discloses transformation of 9.alpha.-hydroxy steroids to .DELTA..sup.9(11) steroids by reaction with an N-haloamide or N-haloimide under anhydrous conditions, in a base, with anhydrous sulfur dioxide. Examples 27 and 28 disclose transformation of 9.alpha.-hydroxyprogesterone with yields of 30.3% and 72.2%, respectively. Bromine, sulfur dioxide and an organic base produce the same result, as does an N-haloamide, sulfur dioxide and an organic base, see Great Britain Pat. No. 1,198,749. This process was tested on 9.alpha.-hydroxyandrostenedione (I), see Preparations 4 through 6. GC analysis indicates that the product is a mixture of androsta-4,9(11)-diene-3,17-dione (III) and androsta-4,8-diene-3,17-dione. The problem with this process is that the androsta-4,9(11)-diene-3,17-dione (III) isomer makes up at best approximately 65% of the reaction product.
Therefore, the prior art discloses various methods to produce .DELTA..sup.9(11) -steroids from 9.alpha.-hydroxy steroids. Preparations 1 through 6 show that when these processes were applied to 9.alpha.-hydroxyandrostenedione (I) they produced at best a 65-35 mixture and usually a 50--50 mixture of androsta-4,9(11)-diene-3,17-dione (III) and androsta-4,8-diene-3,17-dione. These isomeric olefinic steroids are very difficult, expensive, and impractical to separate at best. The process of the present invention transforms 9.alpha.-hydroxyandrostenedione-type compounds (I) to the corresponding androsta-4,9(11)-diene-3,17-dione-type compounds (III) in virtually quantitative yields (greater than 85%) with a ratio for androsta-4,9(11)-diene-3,17-dione (II) to androsta-4,8-diene-3,17-dione of approximately 98 to 2. This very high yield and high ratio is most surprising and unexpected in view of the prior art methods and is highly advantageous from a commercial point of view.